Project 6: Extreme Longevity in Nematodes: Genes & Environments This project will examine mortality and exceptional survival in the nematode Caenorhabditis elegans. Our overarching hypothesis is that longevity is extremely plastic. Corollaries of this hypothesis are that both genetic and environmental factors can work independently in specifying mortality. Moreover, mortality is controlled segmentally: reduced mortality at one age does not automatically cause similar changes in mortality at all ages. We have some evidence in favor of our main hypothesis and its corollaries but we are not at all sure whether they generally hold, especially as longevity increases. Here we plan a series of experiments to test predictions of these hypotheses. Because of our interest in age-specific mortality and in extreme longevity, all will ultimately analyze populations of 100,000 or more nematodes in several ways. We intend also to build upon extremely exciting results that allow us to predict (on the second day of adult life) those worms destined to live longest in a population of genetically identical individuals. We actually have developed the capability of physically separating out a sub-cohort of long-lived individuals (all worms in the populations are genetically identical), using the COPAS "worm sorter", into a distinct population for subsequent analyses. These studies will reveal the dynamics of hidden heterogeneity of frailty. We will closely examine "late-life" reproductive capabilities in C. elegans with a goal of ascertaining whether "older" worms can reproduce under certain conditions or in certain genetic mutants. This capability also will allow direct assessment of possible artifacts resulting from the effects of induced sterility on subsequent mortality, observed in numerous studies of longevity mutants in C. elegans. We will ascertain the shape of the mortality curves throughout life, focusing on extreme longevity. We will analyze new longevity mutations and combinations of mutations that can quadruple life expectancy and maximum life span. We will study the effect of environmental determinants of extended longevity, such as caloric restriction, hormesis, and drug supplementation in large cohorts of the nematode. We will develop physiological and molecular predictors of extreme longevity.